Measuring properties at the molecular scale presents numerous challenges, due to the sensitivity required, and the presence of many potential sources of noise. In describing sensors for this purpose, it is therefore helpful to be clear about all sources of measurement error. In general, for any system or object that may be measured, a measured state, m, will only be an approximation of the actual system state, a. This may be due to any of a number of factors, such as imperfect signal interpretation reflecting error due to the operation of the sensor, the readout process, or the signal interpretation, and also because contacting the sensor to the system in some cases may perturb the state of the system. That the measured state m is different than the actual state a reflects the measurement error of the combined sensor, readout, and interpretation. Ideally, a sensor system will be constructed to make this measurement error as small as possible.
To measure states at a molecular scale, such as in the case of sequencing a DNA molecule, various efforts have been directed to creating sensor systems in which the sensor device has a “probe” that contacts the molecules of interest, preferably on a single-molecule scale, while other features of the sensor device are on larger nano- or micro-scales for purposes of manufacturing the sensor devices or integrating them into a signal transduction system.
In particular, a biosensor is an analytical device that functionally integrates a biological recognition component into a signal transduction system, to measure properties of biologically relevant molecules, such as DNA, RNA or proteins. That integration provides rapid and convenient conversion of biological events to detectable electrical signals. Of the various electrical biosensing architectures that have been devised, systems based on field-effect transistors (FETs) appear promising because they can directly translate interactions between target molecules (e.g., biological molecules) and the FET surface into detectable electrical signals. In a typical FET device, current flows along a channel that is connected to two electrodes (also referred to as the source and the drain). The channel conductance between the source and the drain can be modulated by a third electrode (also referred to as the gate) that is capacitatively coupled to the channel through a thin dielectric insulating layer. FETs can be used to detect target chemicals and measure chemical concentrations for a wide range of commercial applications. A classical and widely used example is a FET-based pH sensor, used to measure hydrogen ion concentration. This was introduced by Bergveld in the 1970's, and is used in solid-state pH sensors. The general field of ion-sensitive FET (ISFET) devices expands upon that concept for other chemical concentration measurements.
A limitation of current FET-type biosensor systems is their sensitivity. Current biosensor systems are unable to perform single molecule detection and identification. Likewise, they are unable to monitor single molecule reaction dynamics. These sensitivity limitations of FET-type biosensors prevent their use as detectors in important biochemical assays, such as in single molecule sequencing reactions.
Some efforts to improve FET biosensor sensitivity have focused on use of carbon nanostructures, such as carbon nanotubes, to form the channel between electrodes. However, carbon nanostructures pose various obstacles with respect to biosensor functionalization. In particular, there is no way to engineer in attachments sites at specific, desired atomic locations, for the purpose of attaching functional or sensitizing probe molecules. Additionally, present limits on precision, control, and scale of the synthesis of carbon nanostructures pose further challenges with respect to sensitivity and reliable production of individual sensors, establishing high density scalable arrays of sensors, and commercial viability of sensor manufacturing. Current carbon nanotube synthesis methods typically produce structures on a scale of around 100 nm or longer in length, a scale that is likely to pose limitations with respect to sensitivity as well as sensor density on a multi-sensor platform.
Thus, molecular-scale electronic biosensor devices with architectures compatible with increased sensitivity and precision, reliable engineering, and that are further compatible with efficient and commercially-viable manufacturing methods for achieving increased sensor density on a multi-sensor platform, are desirable. Likewise, improved methods of manufacturing such sensor devices are also desirable.